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Recurrent Pregnancy Loss
Mala Arora, Justin C Konje
SECTION 1: DIAGNOSIS
CHAPTER 1:
Terminology Clarified
CHAPTER 2:
Investigation and Management of Recurrent Miscarriage—The One Stop Clinic
INTRODUCTION
Definition of Recurrent Miscarriages and Identification of Causes
Parental Chromosome Abnormalities
Uterine and Cervical Pathology
PROTHROMBOTIC STATES
Antiphospholipid Syndrome (APS)
Inherited Thrombophilias
ENDOCRINOLOGICAL DISORDERS
Hypersecretion of LH
High Androgen Levels
Hyperprolactinaemia
Thyroid Dysfunction
Diabetes Mellitus
Immunological Factors
INFECTIONS
LIFESTYLE FACTORS
MATERNAL SYSTEMIC DISEASE
Setting up a Recurrent Miscarriage Clinic
Follow-up During Pregnancy or When There is a Loss
Treatment of Recurrent Miscarriages
CONCLUSION
CHAPTER 3:
Role of Ultrasound
CRITERIA FOR A PREGNANCY LOSS
Structural Uterine Abnormalities
Luteal Phase Defects and Polycystic Ovaries
Immune Disorders
Performance of Procedures
CONCLUSION
SECTION 2: GENETICS
CHAPTER 4:
Genetic Causes
INTRODUCTION
CHROMOSOMAL CAUSES
Abnormality in Chromosome Number (Aneuploidies)
Structural Abnormalities
Sex Chromosome Mosaicism
SINGLE GENE DISORDERS
INHERITED THROMBOPHILIAS
Factor V Leiden and Activated Protein C Resistance
Prothrombin Gene Mutation (G20210A)
MTHFR Polymorphism and Hyperhomocysteinaemia
SHARING OF HLA-ANTIGENS
HLA-G AND HLA-E-POLYMORPHISMS
GENETIC EVALUATION AND COUNSELLING IN RECURRENT MISCARRIAGES
CONCLUSIONS
CHAPTER 5:
Genomics of Y Chromosome
SUMMARY
INTRODUCTION
DEGENERATION OF THE Y CHROMOSOME
MALE INFERTILITY
INHERITED FERTILITY DISORDERS
RECURRENT MISCARRIAGES
GENETIC COUNSELLING
ACKNOWLEDGEMENTS
CHAPTER 6:
Do Abnormal Sperms Cause Recurrent Pregnancy Loss?
INTRODUCTION
Sperm Factor Resulting in Recurrent Pregnancy Loss
Imprinting of Genomes
UNEXPLAINED RECURRENT PREGNANCY LOSS
Sperm DNA Damage: Decondensation and Fragmentation
DNA Damage to Spermatozoa has Impacts on Fertilisation and Pregnancy
Sperm DNA Fragmentation
Elevated Sperm Chromosome Aneuploidy and Apoptosis
Sperm Chromosome Abnormalities in an Assisted Reproduction Program
CHAPTER 7:
Recurrent Molar Pregnancies
INTRODUCTION
PATHOLOGY OF HYDATIDIFORM MOLES
Genetics of Hydatidiform Moles
Familial Recurrent Hydatidiform Moles
Differential Diagnosis of FRHM
FRHM is Associated with Abnormal Genomic Imprinting
Mapping of the Gene for FRHM
Clinical Significance of FRHM
SUMMARY
ACKNOWLEDGEMENTS
CHAPTER 8:
Very Early Pregnancy Loss
INTRODUCTION
Pre-clinical Pregnancy Loss
Human Chorionic Gonadotropin as a Marker for Pregnancy Loss
The Embryo or the Endometrium?
Understanding Early Pregnancy Loss; Lessons From Cytogenetics
Cytogenetic Techniques
Aneuploidy in Oocytes
Aneuploidy in Spermatozoa
Abnormalities in Zygotes and Preimplantation Embryos
Abnormalities in Clinical Miscarriages and in Liveborn Children
The Contribution of Chromosomal Abnormalities to Early Loss in Humans and Other Organisms
Infertility and Recurrent Early Pregnancy Loss: The Continuation of the Spectrum
Implications for IVF
Conclusion
SECTION 3: IMMUNOLOGICAL CAUSES
CHAPTER 9:
Cytokines and the Success or Failure of Pregnancy
ACKNOWLEDGEMENTS
CHAPTER 10:
Clinical Implications of Immunotherapy
INTRODUCTION
DIAGNOSTIC CRITERIA
PATERNAL LEUCOCYTE IMMUNISATION
Efficacy of Treatment
Mechanism of Action
Side Effects
INTRAVENOUS IMMUNOGLOBULIN
Efficacy of Treatment
Mechanism of Action
Side Effects
CONCLUSIONS
CHAPTER 11:
Endometrium in Recurrent Miscarriages
INTRODUCTION
Dating the Endometrium and Luteal Phase Deficiency
Epithelial and Glandular Endometrium
Uterine Natural Killer Cells
Conclusions
CHAPTER 12:
Antiphospholipid Syndrome
INTRODUCTION
Antiphospholipid Antibodies
Mechanism of Action
Platelets
Endothelium
Annexin V and Placental Coagulant Proteins
Mechanism of Pregnancy Loss
Thrombogenic Effects
Non-Thrombogenic Effects
Diagnosis
Clinical Criteria
Laboratory Testing
Anticardiolipin Antibodies
Lupus Anticoagulant
Other Antiphospholipid Antibodies
Specific Tests for APS
Anti β2 Glycoprotein I Antibodies (β2 GPI)
Classification of APS21
Familial APL Syndrome
Management
Intravenous Immunoglobulin (IVIG)
Conclusions
REFERENCES
SECTION 4: HORMONAL
CHAPTER 13:
Endocrinological Disorders
INTRODUCTION
Endocrinological Factors Contributing to Miscarriage
Hyperprolactinaemia
Thyroid Dysfunction and Diabetes
Hypersecretion of Luteinising Hormone
Follicular Phase Abnormality
Luteal Phase Defect
Stress
Androgen
Obesity
ENDOCRINOLOGICAL EVALUATION IN EARLY PREGNANCY
Progesterone
Human Chorionic Gonadotrophin
Inhibin and Activins
ENDOCRINOLOGICAL TREATMENT
hCG and Progesterone
Steroids
Gonadotropins
Laparoscopic Ovarian Drilling
Metformin
CONCLUSION
CHAPTER 14:
Polycystic Ovarian Syndrome
INTRODUCTION
Incidence
The Corpus Luteum (CL) of Early Pregnancy
The Corpus Luteum (CL) in PCOS
Pathophysiology of Recurrent Pregnancy Loss in PCOS
Management of Recurrent Pregnancy Loss in PCOS
Insulin Lowering Drugs
Progesterone Support
Human Chorionic Gonadotropin (hCG)
Other Recommended Therapies
Conclusion
CHAPTER 15:
Declining Ovarian Function
PATHOPHYSIOLOGY
Causes of POF
DIAGNOSTIC CRITERIA
DYNAMIC TESTS OF OVARIAN RESERVE
Clomiphene Citrate Challange Test (CCCT)
Gonadotropin – Releasing Hormone (GnRH) Agonist Stimulation Test [GAST]
Exogenous FSH Ovarian Reserve Test (EFORT)
MANAGEMENT
PREVENTION OF RECURRENT PREGNANCY LOSSES
CHAPTER 16:
Thyroid and Medical Disorders
DIABETES MELLITUS
THYROID DISORDERS
Other Endocrine Causes of Pregnancy Loss
Polycystic Ovarian Syndrome
INFECTIONS
Malaria
AUTOIMMUNE DISORDERS
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
SYSTEMIC SCLEROSIS
HAEMATOLOGICAL DISORDERS
Endocrine Disorders in Beta Thalassaemia Major
MISCELLANEOUS CAUSES
Severe Maternal Illnesses
Environmental Factors
Drugs
SECTION 5: ANATOMICAL
CHAPTER 17:
Anatomical Factors and Role of Endoscopy
INTRAUTERINE SEPTUM
Operative Techniques: Scissors, Electrosurgery or Laser?
1. Hysteroscopic Metroplasty with Scissors
2. Hysteroscopic Treatment of Complete Uterine Septum
The advantages of hysteroscopic metroplasty using scissors36
Disadvantages36
3. Resectoscopic Division of the Uterine Septum
Advantages36
Disadvantages36
4. Hysteroscopic Metroplasty with Fibreoptic Lasers
Advantages36
Disadvantages36
When to Stop?
POSTOPERATIVE MANAGEMENT
1. Intrauterine Device
2. Antibiotics
3. Hormonal Therapy
4. Follow-up Examination of the Uterine Cavity
5. Residual Septa
COMPLICATIONS
1. Complications Associated with the Distension Medium
2. Traumatic Complications
3. Haemorrhage
4. Infection
5. Uterine Rupture in Subsequent Pregnancy
6. Intrauterine Synechiae
Diethylstilbestrol – Related Uterine Anomalies
INTRAUTERINE SYNECHIAE (Fig. 17.4)
Hysteroscopic Technique
UTERINE POLYPS (Fig. 17.7)
Hysteroscopic Technique
SUBMUCOUS FIBROIDS
1. Intracavitary Fibroids
2. Fibroids with < 50 % Intramural Extension
3. Fibroids with > 50 % Intramural Extension
4. Multiple Submucous Myomas (Fig. 17.12)
Conclusion34
CHAPTER 18:
Do Fibroids Cause Recurrent Pregnancy Loss?
PREVALENCE
AETIOLOGY
Age
Race
Menstrual History
Child Bearing
Oral Contraceptive Pills (OCP)
Medroxyprogesterone Acetate (MPA)
Body Mass Index
Physical Activity
Diet
Family History
Cigarette Smoking
Infectious Agents
Pelvic Inflammatory Disease (PID)
Medical Conditions
GENETICS OF UTERINE FIBROIDS
CYTOKINES AND GROWTH FACTORS
ANATOMIC CLASSIFICATION
DIAGNOSTIC MODALITIES
SYMPTOMS
MYOMAS AND RECURRENT PREGNANCY LOSS
Role of Myomectomy
TREATMENT OPTIONS
SURGICAL
Myomectomy
Abdominal Myomectomy
Hysteroscopic Resection
Uterine Artery Embolisation (UAE)
Myolysis
Percutaneous Laser Ablation
High Intensity Focused Ultrasound (HIFU)
MEDICAL THERAPY
Gonadotropin Releasing Hormone Agonists (GnRHa)
Gonadotropin Releasing Hormone and Add Back Therapy
Tibolone
Gonadotropic Releasing Hormone Antagonists
Danazol
Mifepristone
Selective Estrogen Receptor Modulators (SERMS) Tamoxifen and Raloxifen
Growth Factor Directed Treatment
Interferon
Aromatase Synthetase Inhibitors
Cytotoxic Gene Therapy for Fibroids
RECURRENCE
CONCLUSION
CHAPTER 19:
Cervical Incompetence
INTRODUCTION
AETIOLOGY
CLINICAL FEATURES
Examination
Investigations
Inter-conceptional
During Pregnancy
MANAGEMENT
Primary Prevention
Secondary Prevention (Treatment)
CERCLAGE OPERATIONS
Types
Indications
Contraindications
Absolute
Relative
Route of Approach
Principle
Timing of Operation
Materials Used
Pre-requisites
Procedures
I. McDonald's Operation
II. Shirodkar's Operation
Postoperative Care
On Discharge
Removal of Stitch
Complications
Transabdominal Cerclage (TAC)
Disadvantages
CURRENT EVIDENCE ON CERCLAGE
OTHER UNCOMMON PROCEDURES
CONCLUSION
SECTION 6: HAEMATOLOGICAL CAUSES
CHAPTER 20:
Inherited Thrombophilias
HAEMOSTATIC PATHWAYS IN NORMAL PREGNANCY
DEFINITION AND INCIDENCE
INHERITED THROMBOPHILIA—COMMON TYPES
ANTITHROMBIN III DEFICIENCY
PROTEIN C DEFICIENCY
FACTOR V LEIDEN MUTATION (FVL)
PROTEIN S DEFICIENCY
PROTHROMBIN GENE MUTATION
HYPERHOMOCYSTEINAEMIA
PATHOPHYSIOLOGY OF PREGNANCY LOSS IN THROMBOPHILIA
THROMBOPHILIA AND PREGNANCY LOSS
THROMBOPHILIA AND RECURRENT PREGNANCY LOSS
TESTING FOR THROMBOPHILIA
TREATMENT
PRACTICAL RECOMMENDATIONS
FUTURE RESEARCH
CONCLUSIONS
CHAPTER 21:
Thromboelastography and Recurrent Miscarriage
INTRODUCTION
THROMBOELASTOGRAPHY
THROMBOELASTOGRAPHY AND RECURRENT MISCARRIAGE
SECTION 7: INFECTIVE CAUSES
CHAPTER 22:
Bacterial Vaginosis
MECHANISM OF MISCARRIAGES IN BV
Mechanism of Preterm Birth in BV and Current Evidence
Immunomodulatory Effects of BV
Evidence that Infection is Related to PPROM
Prevention of PTL / PPROM in Subsequent Pregnancies
Treatment
Conclusion
CHAPTER 23:
Genital Tuberculosis
INFECTIONS AND PREGNANCY LOSS
Infection Load
PATHOPHYSIOLOGY OF TB
IMMUNOLOGY OF PREGNANCY LOSS
PATHOGENESIS OF PREGNANCY LOSS
Personal Study
Results
SECTION 8: MISCELLANEOUS CAUSES
CHAPTER 24:
Role of Micronutrient
HYPERHOMOCYSTEINAEMIA
WATER-SOLUBLE VITAMINS
VITAMINS SUPPORTING ENERGY METABOLISM
Thiamine
Riboflavin
Niacin
VITAMINS REQUIRED FOR SYNTHESIS OF NEW TISSUES
Pyridoxine(B6)
Folic Acid
Vitamin B12
Vitamin C
FAT-SOLUBLE VITAMINS
Vitamin D
Vitamin A
Vitamin E
Vitamin K
MINERALS
Iron
Calcium
Zinc
OTHER MINERALS
Phosphorus
Magnesium
Iodine
Fluoride
Copper
Selenium
Chromium
CONCLUSION
CHAPTER 25:
Role of Stress in RPL
INTRODUCTION
Influence of Stress on Pregnancy-Related Immune Mediators
Influence of Stress on Hormones Relevant for Reproduction
Role of Stress-related Neurotransmitter in Reproduction
Stress and Cell Adhesion Molecules
Stress and Antioxidants
Influence of Stress on Late Pregnancy Events
ACKNOWLEDGMENTS
CHAPTER 26:
Embryo Morphology in Repeated ART Failures
INTRODUCTION
SPERM DEFECTS
Sperm Centrosome
OOCYTE ABNORMALITIES
ABNORMAL SPERM INCORPORATION AND FERTILISATION
Sperm Incorporation
Pronuclear Aberrations
Dispermy, Digyny and Polypoidy
ABNORMAL CLEAVAGE EMBRYOS
Genome Activation and Embryonic Blocks
Mosaicism
Abnormal Morulae and Blastocysts
Evolution of Embryonic Stem Cells
Cytoplasmic Fragmentation
SECTION 9: TREATMENT OPTIONS
CHAPTER 27:
Critical Review of Current Treatment Options
MANAGEMENT OF GENETIC CAUSE OF RPL
Preimplantation Genetic Diagnosis
Fluorescent In situ Hybridisation (FISH)
Comparative Genomic Hybridisation(CGH)
Foetal Karyotype
TREATMENT OF AUTOIMMUNE CAUSES OF RECURRENT PREGNANCY LOSS
Anti Phospholipid Syndrome (APS)
Heparin and Aspirin
Time of Initiation of Treatment
Dosage Regimens
Risks of Heparin Therapy
Osteoporosis
Heparin Induced Thrombocytopenia
Low Molecular Heparin vs Unfractionated Heparin
Antenatal Care
Results
Steroids
Intravenous Immunoglobulins
ALLOIMMUNE FACTORS
Paternal Leukocyte Immunisation
THROMBOPHILIAS
ANATOMICAL FACTORS
Uterine Anomalies
Unicornuate Uterus
Uterus Didelphus
Bicornuate Uterus
Septate Uterus
Submucus Myoma
Intrauterine Adhesions
Cervical Incompetence
ENDOCRINE FACTORS
Raised LH Levels
Metformin
Luteal Phase Defect
Hyperprolactinaemia
Thyroid Disease: Antithyroid Antibodies
Diabetes
INFECTIONS
SUPPORTIVE CARE
CHAPTER 28:
Role of Tender Loving Care
CHAPTER 29:
Oxidative Stress and Role of Antioxidants
INTRODUCTION
Free Radicals
Reactive Oxygen Species
Reactive Nitrogen Species
Measurement of Oxidative Stress
OXIDATIVE STRESS AND MISCARRIAGE
Antioxidants
Some Important Antioxidants
Vitamin E
Vitamin C
Carotenoids
Beta-carotene
Lycopene
Lyco-O-Mato
L-Arginine
N-acetyl-cysteine (NAC)
CONCLUSION
SECTION 10: IN THE EVENT OF MISCARRIAGE
CHAPTER 30:
Surgical Versus Medical Evacuation
REGIMES FOR MEDICAL MISCARRIAGE
SURGICAL DILATATION AND SUCTION EVACUATION
MANUAL VACUUM ASPIRATION
Combined Medical and Surgical Approach
Second Trimester
Third Trimester
CHAPTER 31:
Grief Counselling
CHAPTER 32:
Medicolegal Implications
TRAUMA AND PERFORATION
Cervical Trauma
Uterine Perforation
Swabs and Packs
Rhesus Immunisation
Infection
WHEN THINGS GO WRONG, WHAT MAY I TELL THE PATIENT?
WHAT DO THE DEFENSE ORGANISATIONS THINK?
PREVENTIVE MEASURES
CLINICAL MANAGEMENT
GENERAL INVESTIGATION PLAN IN CASES OF RECURRENT MISCARRIAGE
SEQUEL OF MISCARRIAGE
Grief
PRETERM LABOUR
CONSENT FOR TREATMENT
Failure to Give Advice/or Giving Wrong Advice
Inability to Make Diagnosis or Error in Making a Diagnosis
Vicarious Liability
SUMMARY AND CONCLUSION
BIBLIOGRAPHY
CASE LAW
APPENDIX: APPENDIX
APPENDIX:
Diagnostic Tests for Autoimmunity Alloimmunity and Thrombophilia
INDEX
TOC
Index
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